Oncogene studies have involved ras encoded proteins and the action of TGF-alpha on the epidermal growth factor receptor. We analyzed chimeras between ras and rap-1A, which encodes a ras-like protein that can suppress ras-transformed cells. The results indicated that the respective effector regions of ras and rap-lA determined whether the protein induced cellular transformation or suppressed transformation, which suggests that rap-1A may suppress ras-induced transformation by interfering with the interaction between ras protein and its effector. Further analysis identified chimeras that were discordant with respect to their sensitivity to GTPase acceleration; some were sensitive to ras-GAP but resistant to NFI, and others were sensitive to cytoplasmic rap-GAP but resistant to membrane rap-GAP. Sensitivity of chimeras to ras-GAP and cytoplasmic rap-GAP was mediated by amino acids that are C-terminal to the effector region. In NIH 3T3 cells, chimeras carrying the p2lras effector region and sensitive only to ras-GAP or only to cytoplasmic rap-GAP were poorly transforming. Thus distinct amino acids of p2lras and p2lrap-1A mediate sensitivity to each of the proteins with GAP activity, and ras-GAP and cytoplasmic rap-GAP are major negative regulators of p2lras and p2lrap-1A, respectively, in NIH 3T3 cells. In the studies with TGF-alpha, we have identified a system in which autocrine stimulation by TGF-alpha is more potent biologically than paracrine stimulation. Using a retroviral vector that encodes the full-length human TGF-alpha precursor protein, NIH 3T3 cells that expressed human TGF-alpha, which was processed and secreted normally, became morphologically transformed and were highly tumorigenic. By contrast to cells within the same petri dish that were not expressing TGF-alpha remained untransformed, as did cells that were treated with saturating concentrations of exogenous TGF-alpha.